This investigation is directed toward the fundamental biology of myocardial cell death in ischemia. It is assumed that understanding the basic processes will benefit the clinical effort to manage ischemic heart disease. Review of the criteria for demonstrating a causal relationship between cell death and any ischemia-produced alteration, and of the requirements of a model to study this relationship, suggests that current tissue and organ models are inadequate. A model using neonatal rat myocardial cells in culture has the requisitie properties. Inhomogeneity of cell types can be alleviated by culture methods designed to kill or inhibit nonmyocardial cells; and manipulation of growth conditions can be used as a probe for the proximate event in cell death. Using a specially-designed chamber, ischemia will be simulated by the combination of anoxia, substrate deprivation, and restriction of bathing medium. The point of cell death, the reversible-irreversible transition, will be defined as the shortest duration of ischemia of constant degree that first produces cells which become necrotic, despite return to normal culture conditions. Phase contrast, light, and electron microscopy will be performed during injury and recovery. To test the hypothesis that ischemic induced alterations in the sarcolemmal calcium-sialic acid-fucose-lipid interaction are important in the genesis of cell death, an integrated study will be performed. 201Tl and 51Cr release, morphologic cell swelling, and changes in total calcium will assess physiologic consequences. Loss or gain of labelled fucose, sialic acid, and lipid will be used to monitor membrane biochemistry and electron microscopic histochemistry with ionic lanthanum and colloidal iron hydroxide will permit morphologic correlation. Conditions will be manipulated to test etiologic significance. Both preliminary work and review of the literature support the contention that this model is feasible and relevant.